5,6-Benzoflavones as cholesterol esterase inhibitors: synthesis, biological evaluation and docking studiesElectronic supplementary information (ESI) available. See DOI: 10.1039/c7md00565bThis research article is dedicated to Dr. Sahil Sharma

• Main Authors: Singh, Jatinder V, Kaur, Anumeet, Bhagat, Kavita, Gupta, Manish K, Singh, Manwinder, Singh, Harbinder, Bedi, Preet Mohinder S
• Format: Article
• Language: English
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c7md00565b

In a continued effort to develop potent cholesterol esterase (CEase) inhibitors, a series of 5,6-benzoflavone derivatives was rationally designed and synthesized by changing the position of the benzene ring attached to the flavone skeleton in previously reported 7,8-benzoflavones. All the synthesized compounds were checked for their inhibitory potential against cholesterol esterase (CEase) using a spectrophotometric assay. Among the series of forty compounds, seven derivatives ( B - 10 to B - 16 ) exhibited above 90 percent inhibition against CEase in an in vitro enzymatic assay. Compound B - 16 showed the most promising activity with an IC 50 value of 0.73 nM against cholesterol esterase. To determine the type of inhibition, enzyme kinetic studies were carried out for B - 16 , which revealed its mixed-type inhibition approach. Moreover, to figure out the key binding interactions of B - 16 with the amino acid residues of the enzyme's active site, molecular protein-ligand docking studies were also performed. B - 16 completely blocks the catalytic assembly of CEase and prevents it from participating in the ester hydrolysis mechanism. The favorable binding conformation of B - 16 suggests its prevailing role as a CEase inhibitor. Overall, the study showed that the cis -orientation of ring A with respect to the carbonyl group of ring C is responsible for the potent CEase inhibitory activity of the newly synthesized compounds. A library of forty 5,6-benzoflavone derivatives was synthesized and evaluated for their inhibitory potential against cholesterol esterase (CEase) enzyme.